Both T cell and B cell immune responses to HCV are being investigated. Previously we developed and characterized human and mouse monoclonal antibodies to the HCV structural genes; core, E1 and E2 using recombinant baculovirus expressed antigens. We have shown that the antibodies ot E1 and E2 can bind to native virion and antibody to core can bind to detergent treated virion.T cell studies are continuing in an effort to identify both cytotoxic T cell and helper T cell epitopes. We are studying the proliferative and CTL responses of patients with chronic HCV infections to peptide antigens and antigens expessed by recombinant DNA systems. We identified a CTL epitope in the core region that is recognized by both mice and humans. BALB/c and C57BL/6 mice were immunized with a series of core region peptides. The eiptope in mice was further defined by a series of 7 decapeptides overlapping 9 residues and the epitope was further defined by a series of LMGYIPLVGA. Eight patients with HCV infections were also studied and two of them were found to react with C7 and to a nonapeptide only one residue removed from the mouse epitope. Both of these patients were HLA-A2 and the nonapeptide DLMGYPLV contains a consensus HLA-A2 binding motif xLxxxxxV. Sindbis virus replicons expressing HCV antigens have been useful in these studies.Several approaches to vaccine development have been taken. Sindbis replicons expressing the structural proteins or the nonstructural proteins of HCV have been tested as potential vaccines in chimpanzees. Following 3 injections, there was a very weak antibody response but not protection against a live virus challenge. Naked DNA vaccines ha~e been prepared that express the E2 glycoprotein of HCV. This DNA vaccine induced an antibody response in 1 out of 3 mice injected IM. A series of these expressions constructs coding for both the structural and nonstructural proteins of how HCV are now being prepared and tested in mice.